FSD1 inhibits glioblastoma diffuse infiltration through restriction of HDAC6-mediated microtubule deacetylation.

in Science China. Life sciences by Dake Xiao, Haowen Ran, Lishu Chen, Yuanyuan Li, Yan Cai, Songyang Zhang, Qinghui Qi, Huiran Wu, Cheng Zhang, Shuailiang Cao, Lanjuan Mi, Haohao Huang, Ji Qi, Qiuying Han, Haiqing Tu, Huiyan Li, Tao Zhou, Fangye Li, Ailing Li, Jianghong Man

TLDR

  • Microtubule deacetylation, mediated by the protein FSD1, plays a crucial role in promoting diffuse infiltration of glioblastoma multiforme (GBM) cells. Targeting FSD1 or its phosphorylation pathways may be a potential therapeutic strategy for improving clinical outcomes in GBM patients.

Abstract

The infiltration of glioblastoma multiforme (GBM) is predominantly characterized by diffuse spread, contributing significantly to therapy resistance and recurrence of GBM. In this study, we reveal that microtubule deacetylation, mediated through the downregulation of fibronectin type III and SPRY domain-containing 1 (FSD1), plays a pivotal role in promoting GBM diffuse infiltration. FSD1 directly interacts with histone deacetylase 6 (HDAC6) at its second catalytic domain, thereby impeding its deacetylase activity on α-tubulin and preventing microtubule deacetylation and depolymerization. This inhibitory interaction is disrupted upon phosphorylation of FSD1 at its Ser317 and Ser324 residues by activated CDK5, leading to FSD1 dissociation from microtubules and facilitating HDAC6-mediated α-tubulin deacetylation. Furthermore, increased expression of FSD1 or interference with FSD1 phosphorylation reduces microtubule deacetylation, suppresses invasion of GBM stem cells, and ultimately mitigates tumor infiltration in orthotopic GBM xenografts. Importantly, GBM tissues exhibit diminished levels of FSD1 expression, correlating with microtubule deacetylation and unfavorable clinical outcomes in GBM patients. These findings elucidate the mechanistic involvement of microtubule deacetylation in driving GBM cell invasion and offer potential avenues for managing GBM infiltration.

Overview

  • The study investigates the role of microtubule deacetylation in promoting glioblastoma multiforme (GBM) diffuse infiltration, which contributes to therapy resistance and recurrence.
  • The researchers identify fibronectin type III and SPRY domain-containing 1 (FSD1) as a crucial mediator of microtubule deacetylation, which is downregulated in GBM tissues.
  • The study aims to elucidate the mechanisms underlying GBM cell invasion and identify potential therapeutic targets for managing GBM infiltration.

Comparative Analysis & Findings

  • The researchers find that FSD1 directly interacts with histone deacetylase 6 (HDAC6) at its second catalytic domain, preventing microtubule deacetylation and depolymerization.
  • Phosphorylation of FSD1 by CDK5 disrupts this inhibitory interaction, allowing HDAC6 to deacetylate α-tubulin and facilitate microtubule deacetylation.
  • Increased FSD1 expression or interference with FSD1 phosphorylation reduces microtubule deacetylation, suppresses invasion of GBM stem cells, and mitigates tumor infiltration in orthotopic GBM xenografts.

Implications and Future Directions

  • The study's findings suggest that targeting FSD1 or its phosphorylation pathways may be a potential therapeutic strategy for managing GBM infiltration and improving clinical outcomes.
  • Future studies could investigate the efficacy of FSD1-targeting therapies in clinical trials and explore the molecular mechanisms underlying FSD1's role in GBM cell invasion.
  • Further research could also focus on identifying additional therapeutic targets or combinations that synergize with FSD1-targeting strategies to effectively manage GBM infiltration.
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